European cancer drug approvals under scrutiny for high risk of bias

By Samantha Black, PhD, The Science Advisory Board editor in chief

September 19, 2019 -- Nearly half of all cancer drugs approved in Europe between 2014 and 2016 were deemed high risk of bias, indicating treatment effects may have been exaggerated. These were the findings of a study conducted by researchers at 7 institutions in the UK and US and published in BMJ on September 18.

The goal of the research was to examine design characteristics, risk of bias, and reporting adequacy of randomized controlled trials of cancer drugs approved by the European Medicines Agency (EMA). The evidence provided in this study builds on previous claims that drug approvals in Europe lack sufficient scientific evidence.

The European Union's EMA has a 'gold standard' for evaluating treatment effectiveness based on randomized controlled trials. A team of international researchers examined the design, risk of bias, and reporting of randomized controlled trials that supported European approvals of cancer drugs from 2014 to 2016 to determine if any of the factors distort treatment efficacy and therefore validity of findings.

During this period, the EMA approved 32 new cancer drugs on the basis of 54 studies. Of these, 41 (76%) were randomized controlled trials; 39 had available publications and were therefore included in the study. Only seven of the approvals were supported by two or more randomized controlled trials.

Only 10 trials (26%) measured overall survival as a main (primary) endpoint. The remaining 29 trials (74%) evaluated indirect measures of clinical benefit, such as free survival, evaluated disease response, event-free survival, or safety, which do not always reliably predict whether a patient will live longer or have a better quality of life.

23 randomized controlled trials had some concerns because of deviations from intended interventions, which reflected either lack of blinding or risk of compromised blinding. 10 trials were judged to be at high risk of bias owing to missing outcome data and seven because of measurement of the outcome.

Overall, 19 trials (49%) were judged to be at high risk of bias because of deficits in their design, conduct, or analysis. Trials that evaluated overall survival were at lower risk of bias than those that evaluated surrogate measures of clinical benefit.

Regulators identified additional problems with 10 of the 32 new drugs (31%) approved over this period, but these concerns rarely surfaced in the scientific literature. Overall, the content and consistency of reporting varied between the two sources.

The findings of the study confirm the need to improve the design, conduct, analysis and reporting of cancer drug clinical trials. The researchers call for regulatory action to ensure pharmaceutical companies routinely evaluate their products responsibly. They also advocate for the use of overall survival as a primary endpoint in cancer drug trials because it has an inherent low risk of bias.

The study urges policymakers, researchers, and clinicians "to carefully consider risk of bias in pivotal trials that support regulatory decisions, and the extent to which new cancer therapies offer meaningful benefit to patients."


Limitations of the study include: did not include clinical study reports, evaluated "risk" of bias rather than bias itself, some of the bias might be unavoidable because of the complexity of cancer trials.

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